RESUMO
We report on two unprecedented cases of pseudoexon (PE) activation in the DMD gene resulting from pure intronic double-deletion events that possibly involve microhomology-mediated mechanisms. Array comparative genomic hybridization analysis and direct genomic sequencing allowed us to elucidate the causes of the pathological PE inclusion detected in the RNA of the patients. In the first case (Duchenne phenotype), we showed that the inserted 387-bp PE was originated from an inverted â¼57 kb genomic region of intron 44 flanked by two deleted â¼52 kb and â¼1 kb segments. In the second case (Becker phenotype), we identified in intron 56 two small deletions of 592 bp (del 1) and 29 bp (del 2) directly flanking a 166-bp PE located in very close proximity (134 bp) to exon 57. The key role of del 1 in PE activation was established by using splicing reporter minigenes. However, the analysis of mutant constructs failed to identify cis elements that regulate the inclusion of the PE and suggested that other splicing regulatory factors may be involved such as RNA structure. Our study introduces a new class of mutations in the DMD gene and emphasizes the potential role of underdetected intronic rearrangements in human diseases.
Assuntos
Distrofina/genética , Éxons/genética , Íntrons/genética , Distrofia Muscular de Duchenne/genética , Mutação , Adulto , Pré-Escolar , Rearranjo Gênico , Humanos , Masculino , Splicing de RNARESUMO
Transient neonatal myasthenia gravis (TNMG) and neonatal lupus are rare conditions due to the transplacental passage of antibodies. We describe a unique case of TNMG, revealing a myasthenia gravis (MG) associated with systemic lupus erythematosus (SLE) in the mother. J. M., 8 days of age, was admitted for jaundice. Examination revealed poor sucking, facial weakness, and hypotonicity. TNMG was confirmed with a high level of antiacetylcholine receptor antibodies in the infant and his mother. No sign of neonatal lupus was observed. Clinical recovery was obtained. The elder brother had autism. In case of previous maternal MG, a low percentage of infants develop TNMG (10 to 20%), but monitoring is required at birth. Improvement is usually obtained within 3 weeks. No correlation has been found between maternal symptoms, antibodies titer, and signs of TNMG. Most cases of neonatal lupus are associated with positive anti-SSA/SSB antibodies in the mother. Both conditions, MG and SLE, are reported, but pregnancies are very few. Autism in the brother focuses on its relationship with immune diseases.
Assuntos
Lúpus Eritematoso Sistêmico/diagnóstico , Miastenia Gravis Neonatal/complicações , Miastenia Gravis/diagnóstico , Anticorpos Antinucleares/sangue , Feminino , Antígenos HLA/genética , Haplótipos , Humanos , Recém-Nascido , Lúpus Eritematoso Sistêmico/imunologia , Masculino , GravidezRESUMO
Myoclonus dystonia is a rare movement disorder caused by mutations in the SGCE gene on chromosome 7q21 (DYT11) encoding the epsilon-sarcoglycan. Myoclonus is present in almost all patients and affects most often neck, trunk and upper limbs. Dystonia is present in about half of the patients. The mode of inheritance is autosomal dominant with variable clinical expression and maternal imprinting. Onset is usually in childhood or adolescence. Alcohol might relieve symptoms. We present a 33 month old girl and her twin brother with disabling involuntary jerky movements during intentional tasks. Family history of this French family was positive for the paternal uncle, his two daughters and the paternal great grandfather. Sequencing of the SGCE gene revealed a novel nonsense mutation c.942C>A (p.Tyr314X) in exon 7, confirming the diagnosis of myoclonus dystonia. Treatment with valproic acid significantly reduced myoclonic episodes and ameliorated life quality.
Assuntos
Doenças em Gêmeos , Mutação/genética , Mioclonia/genética , Sarcoglicanas/genética , Gêmeos Dizigóticos , Pré-Escolar , Eletroencefalografia , Feminino , França , Humanos , Imageamento por Ressonância Magnética/métodosRESUMO
Charcot-Marie-Tooth disease type 1C (CMT1C) is caused by mutations in the small integral membrane protein of the lysosome/late endosome (SIMPLE). We analyzed the coding sequence of SIMPLE in DNA of 53 unrelated cases of dominant demyelinating CMT disease with no mutations in PMP22, GJB1, MPZ, EGR2, and NEFL genes. Four different missense mutations were observed in six families. The mutation Gly112Ser was found in two families confirming its frequent occurrence in SIMPLE mutations. Three novel mutations were also identified: Ala111Gly (two families), Pro135Ser, and Pro135Thr. Familial studies revealed that all carriers of mutations (n = 38), aged from 1 to 78 years, were symptomatic, notably children under 10 years (n = 8). Motor conduction velocities in the median nerve ranked from 16.4 to 32.8 m/s (n = 20). In our series of 968 unrelated dominant demyelinating CMT cases (1992-2005), the percentage of SIMPLE mutations was 0.6 (6/968).
Assuntos
Doença de Charcot-Marie-Tooth/genética , Mutação , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Éxons/genética , Saúde da Família , Feminino , Genes Dominantes/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/análise , Linhagem , Fenótipo , Estudos Retrospectivos , Análise de Sequência de ProteínaRESUMO
Complex chromosome rearrangements (CCR) are rare structural chromosome aberrations that can be found in patients with phenotypic abnormalities or in phenotypically normal patients presenting, however, recurrent miscarriages or infertility. Conventional karyotype generally allows their identification. However, molecular cytogenetic methods can reveal subtle rearrangements. We report, here, the identification of an unbalanced maternally inherited CCR in a boy with multiple congenital malformations and delayed development. High-resolution karyotype completed by molecular cytogenetic prompted us to precise the rearrangements. The healthy mother was found to carry a balanced de novo CCR that implicates four chromosomes (8, 10, 11 and 16), six breakpoints, three translocations and an insertion. The malsegregation of this CCR had led, in her son, to partial 10p12.3 to 10p14 deletion, a chromosomal region associated with the DiGeorge like phenotype.
Assuntos
Anormalidades Múltiplas/genética , Aberrações Cromossômicas , Deficiências do Desenvolvimento/genética , Deleção Cromossômica , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 8/genética , Síndrome de DiGeorge/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , Fenótipo , Gravidez , Translocação GenéticaRESUMO
Although the majority (65%) of boys with Duchenne muscular dystrophy (DMD) carry a deletion in the dystrophin gene, finding mutations in the remaining families is vital for counselling. We have provided a comprehensive mutation service as a national referral centre for France for over 10 years and we report here our experience. Mutation screening is on mRNA from a muscle biopsy. We have detected 79 mutations in 89 samples referred with a diagnosis of DMD, which is the most comprehensive survey to date of the full range of nondeletion mutations. Although some mutations were nonsense mutations, some frameshift mutations and some splicing mutations, all of them led to the generation of premature stop codons or a shortened product which could be detected using the Protein Truncation Test. We recommend a protocol which is robust and sensitive applied to the entire coding region reverse-transcribed from dystrophin transcripts from muscle biopsy.